Delivery of nutrients to tissues is dependent upon blood flow and diffusion of nutrients from the vascular space to the interstitium. While substantial previous research has examined factors that regulate myocardial perfusion, there has been relatively little investigation of vascular permeability of the coronary vascular bed. Furthermore, it has recently become apparent that endothelial regulation of vascular tone may be abnormal in several commonly encountered disease states. Whether another important function of the endothelium, regulation of vascular permeability, is also abnormal in these disease states is not known. I have developed a technique for examining permeability of intact, freely beating hearts. During the five year period of this award, this technique will be employed to investigate the permeability of the coronary vasculature in several different states of endothelial dysfunction. These conditions include ischemia with subsequent reperfusion, pressure induced left ventricular hypertrophy, coronary atherosclerosis, and coronary vascular beds which are dependent upon mature collaterals. Each of these conditions have been associated with abnormal endothelial modulation of vascular smooth muscle tone. These studies, in addition to permitting me to develop new research techniques, will investigate the role of the endothelium in regulating coronary vascular permeability (and hence myocardial nutrient delivery), as well as how coronary permeability changes when the endothelium becomes dysfunctional.